The key to understanding Alzheimer's disease (AD) is determining the etiology and pathogenesis of neuron degeneration in specific brain regions. A growing body of evidence indicates that increased free radical-mediated damage to neurons plays a role in AD and, has been, and is being used as a basis of therapeutic and prevention trials in AD. Because of the critical role of DNA and RNA in cellular function, oxidative damage to both may be important in neuron degeneration in AD. The basic hypothesis of this proposal is that oxidative damage to DNA and RNA and faulty DNA repair are present in the brain of AD and play a role in the pathogenesis of neuron degeneration. Specific aim 1 will address the hypothesis that DNA and RNA base adducts and aldehyde-DNA adducts are increased and base excision repair (BER) and mismatch repair (MMR) are altered in early and late stage AD in brain regions where neurodegenerative changes are most pronounced. Short post-mortem autopsies of longitudinally evaluated AD and control subjects will be used in this study. Specific aim 2 will address the hypothesis that mutations in the MMR genes MSH2 and MLH1 are present in the AD brain in early and late stage AD patients. Specific aim 3 will test the hypothesis that over-expression of helicase and decreased 8-oxyguanine glycosylase in cultured SY5Y cells will increase their susceptibility to oxidative stress. Specific aim 4, building on our published data, will test the hypothesis that proteasome inhibition will increase DNA and RNA oxidation and decrease BER in cultured neurons. Specific aim 5 will use APP/PS1 and PS1 mutant mice and cell cultures to test the hypothesis that Abeta deposition causes increased DNA and RNA oxidation and decline in BER. This project will provide new insight into DNA and RNA oxidation and RNA repair in the brain in AD and define some of the mechanisms involved in these processes in cell culture systems and experimental mutant mice models. It has the potential of identifying molecular targets for development of therapeutic agents aimed at reducing neuron injury and improving outcomes in AD.